Insulin secretion from islet β-cells is initiated by the cholinergic parasympathetic stimulation of β-cells (the so-called “cephalic phase”) and subsequently potentiated during the enteric “absorptive phase” (D'Alessio et al., 2001, J. Clin. Endocrinol. Metab., 86:1253-1259). In response to mechanical and chemical sensor stimulation along the digestive tract, intestinal hormones like the incretins GLP-1 (glucagon-like peptide-1) and GIP (gastric inhibitory peptide) potentiate insulin secretion directly and indirectly, through neuronal stimulation (the “incretin effect”) (Karlsson et al., 1992, Eur. J. Pharmacol., 213:145-146; Balkan et al., 2000, Am. J. Physiol. Regul. Integr. Comp. Physiol., 279:R1449-1454). Progressively, nutrient absorption and blood glucose rise stimulate insulin secretion directly (“post absorptive phase”) (Straub et al., 2002, Diabetes Metab. Res. Rev., 18:451-463). Altogether, different secretagogues act synergistically and trigger the adequate biphasic release of insulin from β-cells. These secretagogues reach islet endocrine cells through the vascular and neural networks. Pancreas innervation consists of parasympathetic and sympathetic efferent fibers, which are branches of the parasympathetic vagus nerve and the sympathetic splanchnic nerves. The vagal input stimulates insulin secretion via cholinergic (i.e. mediated by acetylcholine, Ach) or non-cholinergic mechanisms. Sympathetic postganglionic terminal nerves release noradrenaline or other peptides on endocrine cells repressing insulin and somatostatin secretion, and promoting glucagon release. The afferent sensory fibers innervate the periphery of islets and release peptides, like the calcitonin gene-related peptide (CGRP) repressing insulin secretion (Pettersson and Ahren, 1990, Diabetes Res., 15:9-14).
Insulin secretion insufficiency is responsible for diabetes mellitus (DM). There are two major forms of diabetes mellitus: insulin-dependent (Type I) diabetes mellitus (IDDM) which accounts for about 5 to 10% of all cases, and non-insulin-dependent (Type II) diabetes mellitus (NIDDM or T2DM) which accounts for roughly 90% of all cases. In type I diabetes, β-cell loss is due to an autoimmune reaction. In type II diabetes, increased peripheral insulin resistance challenges the functional β-cell mass: after an initial attempt at overriding the increased insulin demand, β-cell function and number decline progressively, resulting in a large spectrum of conditions that require different prescriptions. Diabetes mellitus affects more than 150 million adults and is one of the leading causes of mortality in the world. Generally, when T2DM is diagnosed, global β-cell function is already reduced by about 50%.
Enhancement of insulin secretion in type II diabetic patients is promoted with drugs such as sulfonylureas, thiazolidinediones (TZD) or GLP-1 receptor agonists, but these treatments do not prevent β-cell exhaustion. Oral anti-diabetics (insulin sensitizers and secretagogues) are found useful during the first stages of the disease when insulin resistance predominates and an insulin pancreatic reserve is still available. However, as pancreatic impairment progresses, basal insulin level starts to be an essential parameter to control for achieving metabolic control in patients. At a later stage of T2DM progression, only a basal-bolus regimen of insulin is able to maintain homeostasis in most patients. Currently, no treatment can stably restore a physiological profile of insulin secretion, leading to diabetes progression and development of serious complications.
Therefore, there is huge heath and economical needs for the development of new treatments for managing insulin secretion insufficiency and in particular new treatment for diabetes mellitus, notably T2DM.
Nogo-A, also known as reticulon-4 or neurite outgrowth inhibitor, is a high molecular weight membrane synaptic protein mostly expressed in the central nervous system (CNS), notably in oligodendrocytes and in subsets of neurons (Chen et al., 2000, Nature, 403:434-439). Nogo-A expression is not restricted to the CNS, but is also found in human skeletal muscle cells (Jokic et al., 2005, Ann. Neurol., 57:553-556). In the intact CNS, Nogo-A appears to have a stabilizing, growth controlling role (Montani et al., 2009, J. Biol. Chem., 284:10793-10807). Nogo-A regulates neurite growth and cell migration (Chen et al., 2000, above). In particular, Nogo-A was shown to restrict neuronal regeneration in the injured adult spinal cord and brain, and to limit plastic rearrangements and functional recovery after large CNS lesions (Schwab, 2004, Curr. Opin. Neurobiol., 14:118-124; Cafferty et al., 2006, J. Neurosci., 26:12242-12250). The growth inhibitory action of Nogo-A is mediated by cytoskeletal regulators, such as Rho GTPases or cofilin (Montani et al., 2009, above). Nogo-A and its receptor (NgR) are also found in synapses, where they may influence synapse stability and function (Aloy et al., 2006, Brain Cell Biol., 35, 137-56).
Nogo-A antagonists have been developed to promote CNS axonal regeneration and functional recovery after spinal cord injury (EP1711530; WO2004/052932; Walmsley et al., 2007, Current Pharmaceutical Design, 13(24), pp. 2470-2484(15); Yang et al., 2009, Annals of Neurology, 999, 999A).